Sulfenyl derivatives of 7-aminocephalosporanic acid

ABSTRACT

Sulfenyl derivatives of 7-aminocephalosporanic acid are prepared by the reaction of 7-aminocephalosporanic acid with an alkyl-, trihaloalkyl-, or aralkylsulfenyl halide. The products have antibacterial activity.

United States Patent [191 Nudelman Sept. 23, 1975 SULFENYL DERIVATIVESOF [56] References Cited 7-AMINOCEPHALOSPORANIC ACID TED STATES PATENTS[75] In ento Abraham Nudelman. Rehovot. 3,828,037 8/1974 De Marinis260/243 c Israel [73] Assignee: American Home Products PrimaryExaminerfNicholas Rizzo Corporation, New York NY- Attorney, Agent, orFirm-David E. Frankhouser 22 F'] d: M 1 1974 1 M 57 ABSTRACT [21] Appl'447414 Sulfenyl derivatives of 7-aminocephalosporanic acid are preparedby the reaction of 7-aminocephalospo- [52] US. Cl. 260/243 C; 424/246ranic acid with an alkyl-, trihaloalkyl-, or aralkylsulfe- [51] Int. Cl.C07D 501/18 nyl halide. The products have antibacterial activity. [58]Field of Search 260/243 C 4 Claims, No Drawings SULFENYL DERIVATIVES OF7-AMINOCEPHALOSPORANIC ACID The invention for which a patent is soughtcomprises chemical compounds of the formula:

R-S-XH S o ll L N C11,,0CCH.

made by reaction of the carboxylic acid moiety thereof with a suitablystrong base. Among the salts contemplated are the alkali metal salts(e.g. sodium or potassium), alkali earth metal salts (e.g. calcium,magnesium, or barium) or organic salts, such as ammonia, trialkylamine,or N-methylmorpholine salts.

Special mention is made of the following specific embodiments: V

7-( l l ,1-trichloromethanesulfenamido)-cephalosporanic acid;

7-( l ,1 ,1-trifluoromethanesulfenamido)-cephalosporanic acid; and

7-( a-toluenesulfenamido)cephalosporanic acid; and

the salts thereof.

The compounds of the invention possess anti-bacterial activity asdemonstrated by standard in vitro bacteriological test procedures. Thecompounds can therefore be used to control the growth of bacteria thatare sensitive to the particular compound employed.

The compounds of the invention are prepared by the interaction of7-aminocephalosporanic acid, with a sul- .fenyl halide of the formula:

'wherein R has the meanings as set forth hereinabove, and X is achlorine or bromine atom; in the presence of a base (e.g.triethylamine). The condensation reaction is carried out in areaction-inert organic solvent (e.g. dichloromethane) at a temperatureof about 0C.

The method of preparation of the compounds of Formula I and the methodfor eliciting the antibacterial activity thereof are illustrated in thefollowing examples:

EXAMPLE I 7-( l 1 l -Trich1oromethanesulfenamido)-Cephalosporanic AcidTo a solution of 7-aminocephalosporanic acid (2.72 g, 0.01 moles) andtriethylamine (2.02 g, 0.02 moles) in 100 ml of dichloromethane,trichloromethylsulfenyl chloride (1.86 g, 0.01 moles) is added. Thereaction mixture is stirred at ice temperature for 0.5 hours. It is thenwashed with 3N hydrochloric acid and water, dried over magnesiumsulfate, flash concentrated to 10 ml and precipitated into pentane. Thetitle compound (2.46 g, 58 percent yield), decomposes when heated. NMR:(DMSO- G) ppm 8 2.03 (s,3), 3.54 (broad s, 2), 4.85 (q, 2), 5.07 (d, 1),5.38 (d, 1).

Analysis for: C I-I N Cl O S Calculated: C, 31.33; H, 2.63; N, 6.64; Cl,25.22; S, 15.21 Found: C, 32.17; H, 2.99; N, 6.64; CI, 24.99; S, 14.83

EXAMPLE II 7-( 1 1 ,1-Trifluoromethanesulfenamido)-Cephalosporanic AcidThe title compound is prepared by a similar procedure as that of Example1 from trifluoromethanesulfenyl chloride (1.82 g, 0.0133 mole),7-aminocephalosporanic acid (3.62 g, 0.0133 mole) and triethylamine(2.69 g, 0.0266 mole). The product obtained (1.6 g, 32 percent yield)decomposes when heated. NMR: (DCC1 ppm 8 2.10 (s, 3), 3.52 (broad s, 2),4.9 5.2 (broad band 4).

Analysis for: C H N F O S Calculated: C, 35.48; H, 2.98; N, 7.53 Found:C, 36.10; H, 3.20; N, 7.14

EXAMPLE III 7-(a-Toluenesulfenamido)Cephalosporanic Acid The titlecompound is prepared as described in Example from a-toluenesulfenylbromide, 7-aminocephalosporanic acid and triethyl amine. The productobtained (15 percent yield) decomposes when heated. NMR: (DCCl ppm 62.08 (s, 3), 3.4 (broad s, 2), 4.20 (s, 2), 4.53 (q, 2), 5.1 (q, 2), 7.3(s, 5). The product contains 0.25 mole of dibenzyl disulfide.

Analysis for: C H N S O .O.25 C I-1 8 Calculated: C, 53.99; H, 4.75; N,6.14; S, 17.58 Found: C, 54.07; H, 4.62; N, 6.16; S, 17.24

EXAMPLE IV The in vitro antibacterial activity of the compounds of theinvention can be demonstrated by the agar serial dilution test asdescribed below:

A stock solution of the test compound in sterile 1% phosphate buffer, pH7, at a concentration 2500 pg/ml is prepared. Two-fold dilutions of thestock solution are made by adding appropriate amounts of the buffersolution. One-ml. quantities of each dilution are incorporated into seedagar in sterile petri dishes to give plates containing varyingconcentrations of the test compound. The hardened surface of each plateis inoculated with the test organism and the plates are incubated for 18hours at 35C. The in vitro activity of the compound tested is expressedas the minimal inhibitory concentration (MIC) which is defined as theleast amount of material (,ug/ml) that completely inhibits the testorganism.

When tested according to the aforedescribed procedure, the compoundsdescribed in Examples I, II, and III gave the following results:

MIC (#g/ml. Compound Example I Example 11 E tample lll Bacillussubtilis' 6633 3.90 15.6 31.3 65381 15.6 3.9 31.3 Staphylococcus aureusStaphylococcus aureus Smith 15.6 3.9 31.3 Staphylococcus aureus CHP 31.315.6 62.5 Staphylococcus aureus 53-180 31.3 7.81 62.5 Mycobacteriumsmegmatis 10143 NA NA NA Neisseria catarrhalis 8193 125 250 NAPseudomonas aeruginosa 10145 NA NA NA Escherichia coli 9637 62.5 NA NAEscherichia intermedia 65-1 125 NA NA Salmonella paratyphi 1 1737 31.3NA NA Enterobacter aerogenes 13048 125 NA NA Klebsiella pneumoniae 1003162.5 250 NA Bordetella bronchiseptica 4617 125 125 250 Proteus vulgaris6896 125 125 125 Herellea sp. 9955 62.5 250 250 NA not active up to 250ug/ml.

What is claimed is: wherein R is lower alkyl, trihalomethyl, benzyl,phenl. A compound of the formula: ethyl, or a benzyl or phenethyl groupin which the benzene ring thereof is substituted with a nitro, halogen,cyano, or lower alkyl group, and the alkali metal, alkali earth metal,or ammonia salts thereof. 2. A compound as defined in claim 1 which is7- (1,l,1-trichloromethanesulfenamido)cephalosporanic R- 5-- NH-- 0acid. N CH OCCH 3. A compound as defined in claim 1 which is 7- 0/ 2 31,1,l-trifluoromethanesulfenamido)cephalosporanic acid. 4. A compound asdefined in claim 1 which is 7-mtoluenesulfenamido)cephalosporanic acid.0 1

1. A COMPOUND OF THE FORMULA:
 2. A compound as defined in claim 1 whichis 7-(1,1,1-trIchloromethanesulfenamido)cephalosporanic acid.
 3. Acompound as defined in claim 1 which is7-(1,1,1-trifluoromethanesulfenamido)cephalosporanic acid.
 4. A compoundas defined in claim 1 which is 7-( Alpha-toluenesulfenamido)cephalosporanic acid.